The present invention relates to the delivery of anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing lidocaine, verapamil, diltiazem, isometheptene, or lisuride that are used in inhalation therapy.
There are a number of compositions currently marketed for the treatment of migraine headaches. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients given in such anti-migraine compositions are lidocaine, verapamil, diltiazem, isometheptene, and lisuride.
It is desirable to provide a new route of administration for lidocaine, verapamil, diltiazem, isometheptene, and lisuride that rapidly produces peak plasma concentrations of the compounds. The provision of such a route is an object of the present invention.
The present invention relates to the delivery of anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing lidocaine, verapamil, diltiazem, isometheptene, or lisuride that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride. Preferably, the particles comprise at least 10 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride.
Typically, the aerosol has a mass of at least 10 xcexcg. Preferably, the aerosol has a mass of at least 100 xcexcg. More preferably, the aerosol has a mass of at least 200 xcexcg.
Typically, the particles comprise less than 10 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride degradation products. Preferably, the particles comprise less than 5 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
Typically, where the aerosol comprises lidocaine, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 60 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 40 mg/L.
Typically, where the aerosol comprises verapamil, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 10 mg/L.
Typically, where the aerosol comprises diltiazem, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 45 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 40 mg/L.
Typically, where the aerosol comprises isometheptene, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 200 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 120 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 100 mg/L.
Typically, where the aerosol comprises lisuride, the aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 1.0 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 0.7 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 0.5 mg/L.
Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL or 108 particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.2.
Typically, the aerosol is formed by heating a composition containing lidocaine, verapamil, diltiazem, isometheptene, or lisuride to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, one of lidocaine, verapamil, diltiazem, isometheptene, or lisuride is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least 10 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride.
Typically, the particles comprise at least 5 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride. Preferably, the particles comprise at least 10 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride.
Typically, the condensation aerosol has a mass of at least 10 xcexcg. Preferably, the aerosol has a mass of at least 100 xcexcg. More preferably, the aerosol has a mass of at least 200 xcexcg.
Typically, the particles comprise less than 10 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride degradation products. Preferably, the particles comprise less than 5 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.2.
Typically, where the aerosol comprises lidocaine, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 60 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 40 mg/L.
Typically, where the aerosol comprises verapamil, the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 1.0 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 10 mg/L.
Typically, where the aerosol comprises diltiazem, the delivered aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 45 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 40 mg/L.
Typically, where the aerosol comprises isometheptene, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 200 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 120 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 100 mg/L.
Typically, where the aerosol comprises lisuride, the delivered aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 1.0 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 0.7 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 0.5 mg/L.
Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/ML or 108 particles/mL.
Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 109 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.
Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.
Typically, where the condensation aerosol comprises lidocaine, between 5 mg and 100 mg of lidocaine are delivered to the mammal in a single inspiration. Preferably, between 10 mg and 60 mg of lidocaine are delivered to the mammal in a single inspiration. More preferably, between 20 mg and 40 mg of lidocaine are delivered in a single inspiration.
Typically, where the condensation aerosol comprises verapamil, between 0.5 mg and 50 mg of verapamil are delivered to the mammal in a single inspiration. Preferably, between 1.0 mg and 20 mg of verapamil are delivered to the mammal in a single inspiration. More preferably, between 2.0 mg and 10 mg of verapamil are delivered in a single inspiration.
Typically, where the condensation aerosol comprises diltiazem, between 2.0 mg and 50 mg of diltiazem are delivered to the mammal in a single inspiration. Preferably, between 5 mg and 45 mg of diltiazem are delivered to the mammal in a single inspiration. More preferably, between 10 mg and 40 mg of diltiazem are delivered in a single inspiration.
Typically, where the condensation aerosol comprises isometheptene, between 5 mg and 200 mg of isometheptene are delivered to the mammal in a single inspiration. Preferably, between 10 mg and 120 mg of isometheptene are delivered to the mammal in a single inspiration. More preferably, between 20 mg and 100 mg of isometheptene are delivered in a single inspiration.
Typically, where the condensation aerosol comprises lisuride, between 0.1 mg and 1.0 mg of lisuride are delivered to the mammal in a single inspiration. Preferably, between 0.05 mg and 0.7 mg of lisuride are delivered to the mammal in a single inspiration. More preferably, between 0.1 mg and 0.5 mg of lisuride are delivered in a single inspiration.
Typically, the delivered condensation aerosol results in a peak plasma concentration of lidocaine, verapamil, diltiazem, isometheptene, or lisuride in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).
In a kit aspect of the present invention, a kit for delivering lidocaine, verapamil, diltiazem, isometheptene, or lisuride through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride; and, b) a device that forms a lidocaine, verapamil, diltiazem, isometheptene, or lisuride aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of lidocaine, verapamil, diltiazem, isometheptene, or lisuride.
Typically, the device contained in the kit comprises: a) an element for heating the lidocaine, verapamil, diltiazem, isometheptene, or lisuride composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.